There is a growing concern that naturally existing benign viruses within human population or viruses normally residing in non-human hosts may evolve to efficiently infect and spread through the human population after acquiring sporadic mutations in the wild or being genetically modified in laboratory settings for bioterrorism. Even with enormous advances in the development of diagnostic techniques, several weeks may pass before a novel emerging virus can be identified; and it may take several months (or years) to develop effective virus- specific therapy. Therefore, under the threat of an attack to civilian or military personnel with bioweapons of unknown nature, or immediately after an attack, only broad-spectrum antivirals can be used as a prophylactic treatment to prevent and/or treat infection with an unidentified viral agent. Hundreds of different viruses are able to infect humans; and the severity of the disease may range from asymptomatic opportunistic infections to life-threatening viral diseases. Although the biology, life cycle and pathogenesis of different viruses are widely divergent, the immune system employs mainly the same mechanism of antiviral protection to battle any type of viruses. This mechanism relies entirely on the action of interferons (IFNs). These small secreted proteins are released by virus-infected cells to warn neighboring cells about viral presence and to force these cells to deploy various means of antiviral protection. Thus, we believe that the best therapeutic strategy to deal with viral infections is to enhance protective antiviral forces of the immune system, rather than target an individual virus for therapeutic intervention. There are two types of IFNs, type I IFNs (IFN-/) and recently identified type III IFNs (IFN-?s), that can independently activate rapid innate antiviral protection in various organs. Importantly, recent studies have started to reveal unique biological features of IFN-?s that may make them better antiviral therapeutics than type I IFNs. We have assembled a strong team of investigators with the participation of a pharmaceutical company, the team that has necessary expertise, intellectual property and capability to develop and test IFN-?- based therapeutics for biodefense. In aim 1, we will develop procedures to optimize and scale up production of IFN-?3 and its derivatives for the extensive in vitro and in vivo testing needed to establish its preclinical efficacy. This will include pegylation of IFN-?3 t improve the stability, deliverability and increase safety of IFN- ?3. In other aims, we will test antiviral properties and mechanisms of action of IFN-?3-base antivirals against various viruses in animal models of infection, first at biosafety level 2 (BSL2) and then at BSL3 facilities. The long-term goal of this project is to develop IFN-?-based broad-spectrum antiviral therapeutics and bring them into the clinic.